A placebo-controlled randomized cross-over lovastatin trial in neurofibromatosis type 1 reveals Ras/MAPK modulation of dynamic emotional face processing

Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder characterized by cognitive and socioemotional processing deficits, associated with dysregulation of the Ras/MAPK pathway and alterations in neural inhibition and the GABA system. This study examined the effects of lovastatin, a Ras/MAPK pathway modulator with a direct influence on excitatory/inhibitory (E/I) balance, on neural responses during an emotional recognition task using a randomized, triple-blind, placebo-controlled crossover design. Electroencephalography (EEG) oscillatory responses were recorded pre- and post-intervention, focusing on parietal theta rhythms previously shown to be associated with inhibitory processing and to index dynamic facial emotion recognition.

In this within-subject cross-over design, fifteen individuals with NF1 were pseudorandomly assigned to both the placebo (3 doses of 60 mg) and the lovastatin (3 doses of 60 mg) intervention. Data were collected at pre-intervention, post-placebo and post-lovastatin administration and analyzed using event-related spectral perturbations (ERSP) computed with Morlet wavelets. Lovastatin selectively modulated theta band power (5–6 Hz) during emotional recognition, as reflected by a significant intervention × task interaction and a significant within-session reduction in centroparietal theta oscillations following lovastatin.

No significant effects were observed in alpha (8–11 Hz) or beta (13–20 Hz) bands, nor in theta power during a visual control condition. Given the established role of theta oscillations in face emotion processing, the observed reduction suggests lovastatin influences task-specific oscillatory dynamics. Moreover, these findings provide a mechanistic link between parietal theta oscillations, emotion recognition, and inhibitory regulation.

This novel neurophysiological effect identifies a potential treatment target for NF1 and related neurodevelopmental disorders, including autism (NIH Trial Registration #NCT03826940). This work was supported by the Luso-American Foundation [Prémio FLAD Life Sciences 2020]; and the Foundation for Science and Technology [FCT/UID/4950/2025, DSAIPA/DS/0041/2020, and CEECINSTLA/00026/2022/CP2919/CT0001]. Coimbra Institute for Biomedical Imaging and Translational Research, CIBIT, University of Coimbra, Coimbra, Portugal Diana Costa, Teresa Sousa, Ana Espírito, Ana Dionísio, Marco Simões, Inês Bernardino, Ricardo Martins & Miguel Castelo-Branco Institute for Nuclear Sciences Applied to Health, ICNAS, University of Coimbra, Coimbra, Portugal Diana Costa, Teresa Sousa, Ana Espírito, Ana Dionísio, Inês Bernardino, Ricardo Martins & Miguel Castelo-Branco Institute of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal Intelligent Systems Associate Laboratory (LASI), Guimarães, Portugal Center for Informatics and Systems, CISUC, University of Coimbra, Coimbra, Portugal Correspondence to Miguel Castelo-Branco.

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